1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a well known inducer of Parkinson's disease in primates. We have shown earlier that MPTP and its metabolite, MPP+ (1-methyl-4-phenyl pyridinium ion produced cell death in cultures of neuroblastoma x glioma hybrid cell line NG 108-15 and that this system could serve as a model for studies of the neurodegenerative disease. Since Aiuchi et al.(Neurochem.Int.12: 525, 1988) has shown that tetraphenylborate (TPB) increases the accumulation of MPP+ in mitochondria and thereby potentiates its inhibitory effect on the respiration, we have studied the effect of TPB on MPTP-induced death in NG 108-15 cells. The release of [14C]prelabeled adenine nucleotides were used as a measure of cell death. The concentration of MPTP required to cause a 50% release of adenine nucleotides from the cells during an incubation period of 24 hrs was reduced from 1500 (mu)M to 15 (mu)M, when TPB (100 (mu)M) was added to the medium. The cell death was preceded by a depletion of cell ATP and a 50% depletion was observed when NG 108-15 cells were treated with 1500 (mu)M of MPTP for 12 hrs. However, the concentration of MPTP required was markedly reduced to 0.3 uM in the presence of TPB (100 (mu)M). These results indicate that the potentiation of MPTP-induced neuronal cell death by TPB is possibly caused by an increased loss of cell ATP. Thus, loss of cell ATP is a major factor in the cell death resulting from MPTP treatment. In support of this conclusion, high concentrations of glucose in the medium protects NG 108-15 cells against the MPTP-mediated depletion of cell ATP and the subsequent cell death. It is thus possible to postulate that a reduction in cell ATP may also be responsible for the cell death in dopaminergic neurons in Parkinson's disease. Moreover, the interaction between TPB and MPTP with devastating effects on neuronal cells may indicate that more than one environmental agent may be responsible for Parkinson's disease in humans.